Graduation Date

Spring 5-9-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Aaron Mohs

Abstract

Surgical resection remains to be the primary treatment for the majority of solid tumors, including breast cancer. The complete removal of the primary tumor, local metastases, and metastatic lymph nodes dramatically improve a patient’s treatment outcome and prognosis. Nevertheless, surgeons are limited to tactile and visual cues in distinguishing malignant and healthy tissue. This can result in a positive surgical margin (PSM), which occurs when tumor goes undetected and is left behind in the surgical cavity. PSMs decreases a patient’s prognosis and necessitate additional treatment in the form of surgery, radiation, and chemotherapy. An emerging imaging modality, known as fluorescence-guided surgery (FGS), holds promise for real-time intraoperative tumor detection and reducing PSM rates.

Recently, the Mohs lab has developed an FGS contrast agent composed of a self-assembled hyaluronic acid (HA)-based nanoparticle loaded with the FDA-approved near-infrared (NIR) dye, indocyanine green (ICG), termed NanoICG. The work of this dissertation details the translational development of NanoICG. Using mouse models of triple-negative breast cancer (TNBC), a proof-of-concept study demonstrated that NanoICG improves delivery of ICG to tumors, improving NIR fluorescent signal and intraoperative contrast. These results were expanded upon in a surgical efficacy study that utilized syngeneic, orthotopic murine breast tumors. The efficacy of NanoICG was assessed with survival FGS and compared to free ICG, bright light surgery (BLS), and sham controls. NanoICG significantly-reduced rates of residual disease after FGS and prolonged survival. This was attributed to (1) the superior intraoperative NIR signal that was afforded by NanoICG and (2) the ability of NanoICG to identify small, occult lesions.

In addition to the efficacy study, a 28-day biodistribution and safety assessment of NanoICG was conducted in CD-1 mice. Although biodistribution results demonstrated prolonged retention of NanoICG in the liver and spleen compared to ICG, there was no evidence of hematologic or histologic toxicity. Taken together, the results of these studies conclude that NanoICG is a safe and efficacious FGS contrast agent. Future studies will seek to advance the development via translational animal models (i.e. porcine), investigate mechanisms of tumor uptake and retention, and analyze the pharmacokinetic profile of NanoICG.

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